1. Technical Field
This application relates to the field of biomedical sciences, and in particular relates to methods for lowering lipid levels in mammals. Some embodiments are directed to inhibition comprising administering compounds such as 4-(2-napthylcarboxamido) phenoxyisobutyric acid]; 2-(8-quinolinoxy) propionic acid]; and methylene bis(4,4′-(2-chlorophenylureidophenoxyisobutyric acid)].
2. Description of the Background Art
The Diabetic Control and Complications Trial (DCCT) and UKPDS studies have identified hyperglycemia as the main risk factor for the development of diabetic complications. The Diabetes Control and Complications Trial Research Group N. Engl. J. Med. 329:977-986, 1993; UK Prospective Diabetes Study Group Lancet 352:837-853, 1998. Formation of advanced glycation endproducts (AGEs) has been identified as the major pathogenic link between hyperglycemia and the long-term complications of diabetes. Makita et al., N. Eng. J. Med. 325:836-842, 1993; Bucala and Cerami, Adv. Pharmacol 23:1-33, 1992; Browlee, Nature 414:813-820, 2001; Sheetz and King, J.A.M.A. 288:2579-2588, 2002; Stith et al., Expert Opin. Invest. Drugs 11:1205-1223, 2002.
Non-enzymatic glycation (also known as the Maillard reaction) is a complex series of reactions between reducing sugars and the amino groups of proteins, lipids, and DNA which leads to browning, fluorescence, and cross-linking. Bucala et al., Proc. Natl. Acad. Sci. USA 90:6434-6438, 1993; Bucala et al., Proc. Natl. Acad. Sci. USA 81:105-109, 1984; Singh et al., Diabetologia 44:129-146, 2001. This complex cascade of condensations, rearrangements and oxidation produces heterogeneous, irreversible, proteolysis-resistant, antigenic products known as advanced glycation endproducts (AGEs). Singh et al., Diabetologica 44:129-146, 2001; Ulrich and Cerami, Rec. Prog. Hormone Res. 56:1-2, 2001. Examples of these AGEs are Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), Nε-(carboxymethyl)cysteine (CMC), arg-pyrimidine, pentosidine and the imidazolium crosslinks methyl-gloxal-lysine dimer (MOLD) and glyoxal-lysine dimer (GOLD). Thorpe and Baynes, Amino Acids 25:275-281, 2002; Chellan and Nagaraj, Arch. Biochem. Biophys. 368:98-104, 1999. This type of glycation begins with the reversible formation of a Schiff's base, which undergoes a rearrangement to form a stable Amadori product.
Both Schiff's bases and Amadori products further undergo a series of reactions through dicarbonyl intermediates to form AGEs. Lipid peroxidation of polyunsaturated fatty acids (PUFA), such as arachidonic acid and linoleic acid, also yield carbonyl compounds. Some of these are identical to those formed from carbohydrates, such as MG and GO, and others are characteristic of lipid, such as malondialdehyde (MDA), 4-hydroxynonenal (HNE), and 2-hydroxyheptanal (2HH). See Baynes and Thorpe, Free Rad. Biol. Med. 28:1708-1716, 2000; Fu et al., J. Biol. Chem. 271:9982-9986, 1996; Miyata et al., FEBS Lett. 437:24-28, 1998; Miyata et al., J. Am. Soc. Nephrol. 11:1744-1752, 2000; Requena et al., Nephrol. Dial. Transplant. 11 (supp. 5):48-53, 1996; Esterbauer et al., Free Radic. Biol. Med. 11:81-128, 1991; Requena et al., J. Biol. Chem. 272:17473-14779, 1997; Slatter et al., Diabetologia 43:550-557, 2000. These reactive carbonyl species (RCSs) rapidly react with lysine and arginine residues of proteins, resulting in the formation of advanced lipoxidation endproducts (ALEs) such as Nε-carboxymethyllysine (CML), N-carboxyethyllysine (CEL), GOLD, MOLD, malondialdehyde-lysine (MDA-lysine), 4-hydroxynonenal-lysine (4-HNE-lysine), hexanoyl-lysine (Hex-lysine), and 2-hydroxyheptanoyl-lysine (2HH-lysine). See FIG. 1. Thorpe and Baynes, Amino Acids 25:275-281, 2002; Miyata et al., FEBS Lett. 437:24-28, 1998; Miyata et al., J. Am. Soc. Nephrol. 11:1744-1752, 2000; Uchida et al., Arch. Biochem. Biophys. 346:45-52, 1997; Baynes and Thorpe, Free Rad. Biol. Med. 28:1708-1716, 2000. Since CML, CEL, GOLD and MOLD can result from lipid and carbohydrate metabolism, these chemical modifications on tissue proteins that can serve as biomarkers of oxidative stress resulting from sugar and lipid oxidation. Fu et al., J. Biol. Chem. 271:9982-9986, 1996; Requena et al., Nephrol. Dial. Transplant. 11 (supp. 5):48-53, 1996. The relative role of hyperglycemia versus hyperlipidemia in the chemical modification and pathogenesis of diabetic complications remains uncertain, however. Additionally, several biomarkers of protein modification such as CML and CEL can be derived from either sugar or lipid sources, further complicating the interpretation and analysis of experimental data.
In human diabetic patients and in animal models of diabetes, these non-enzymatic reactions are accelerated and cause accumulation of AGEs on long-lived structural proteins such as collagen, fibronectin, tubulin, lens crytallin, myelin, laminin and actin, in addition to hemoglobin, albumin, LDL-associated proteins and apoprotein. The structural and functional integrity of the affected molecules, which often have major roles in cellular functions, are perturbed by these modifications, with severe consequences on organs such as kidney, eye, nerve, and micro-vascular functions, which consequently leads to various diabetic complications such as nephropathy, atherosclerosis, microangiopathy, neuropathy and retinopathy. Boel et al., J. Diabetes Complications 9:104-129, 1995; Hendrick et al., Diabetologia 43:312-320, 2000; Vlassara and Palace, J. Intern. Med. 251:87-101, 2002.
Current research indicates that reactive carbonyl species such as MGO, GO, GLA, dehydroascorbate, 3-deoxyglucosone and malondialdehyde, are potent precursors of AGE/ALE formation and protein crosslinking. Lyons and Jenkins, Diabetes Rev. 5:365-391, 1997; Baynes and Thorpe, Diabetes 48:1-9, 1999; Miyata et al., J. Am. Soc. Nephrol. 11:1744-1752, 2000; Thornalley st al., Biochem. J. 344:109-116, 1999. In vitro studies further suggest that these carbonyls originate mainly formed from ascorbate and polyunsaturated fatty acids and not from glucose per se. Miyata et al., FEBS Lett. 437:24-28, 1993.
Direct evidence implicates the contribution of AGEs/ALEs in the progression of diabetic complications in different lesions of the kidneys, the rat lens, and in atherosclerosis. Horie et al., J. Clin. Invest. 100:2995-3004, 1997; Matsumoto et al., Biochem. Biophys. Res. Commun. 241:352-354, 1997; Bucala and Vlassara, Exper. Physiol. 82:327-337, 1997; Bucala and Rahbar, in: Endocrinology of Cardiovascular Function. E. R. Levin and J. L. Nadler (eds.), 1998. Kluwer Acad. Publishers, pp. 159-180; Horie et al., J. Clin. Invest. 100:2995-3004, 1997; Friedman, Nephrol. Dial. Transplant. 14 (supp. 3):1-9, 1999; Kushiro et al., Nephron 79:458-468, 1998. Several lines of evidence indicate that hyperglycemia in diabetes causes the increase in reactive carbonyl species (RCS) such as methylglyoxal, glycolaldehyde, glyoxal, 3-deoxyglucosone, malondialdehyde, and hydroxynonenal. “Carbonyl stress” leads to increased modification of proteins and lipids, through reactive carbonyl intermediates forming adducts with lysine residues of proteins, followed by oxidative stress and tissue damage. Lyons and Jenkins, Diabetes Rev. 5:365-391, 1997; Baynes and Thorpe, Diabetes 48:1-9, 1999; Miyata et al., J. Am. Soc. Nephrol. 11:1744-1752, 2000. See FIG. 1.
A number of recent clinical trials such as the DCCT/EDIC, EURODIAB Prospective Complications Study Group, the Hoorn Study and UKPDS, have unanimously identified plasma trigylceride concentrations as an independent risk for development of diabetic complications (retinopathy, nephropathy, cardiovascular disease) in diabetic individuals and in the non-diabetic population. Jenkins et al., Kidney Int. 64:817-828, 2003; Chaturvedi et al., Kidney Int. 60:219-227, 2001; van Leiden et al., Diabetes Care 25:1320-1325, 2002; United Kingdom Prospective Diabetes Study (UKPDS: 10), Diabetologia. 36:1021-1029, 1993. These studies have established a strong correlation between microalbuminuria and levels of plasma triglycerides and cholesterol. Moreover, recent studies on the lipid-lowering effects of pyridoxamine (PM) and aminoguanidine (AG), two known AGE inhibitors in diabetic and hyperlipidemic rats (Degenhardt et al., Kidney Int. 61:939-950; 2002; Alderson et al., Kidney Int. 63:2123-2133, 2003), suggested that there was increased lipid peroxidation in these animals and that PM and AG in fact had lipid-lowering effects. Furthermore, the lipid lowering effects of PM and the correlation of plasma triglycerides and cholesterol with AGEs in skin collagen suggested that lipids might be an important source of AGEs in diabetic rats. Several PM adducts of lipoxidation intermediates of arachidonic acid and linoleic acid were excreted in substantially higher concentrations in the urine of diabetic and hyperlipemic rats treated with PM, suggesting an increase in lipoxidation in these animals. Metz et al., J. Biol. Chem. [August 15, Epub ahead of print], 2003. Based on these results, the authors concluded that lipids could be the primary source of chemical modification of proteins in diabetes and obesity, especially in the presence of hyperlipidemia or dyslipidemia, even in the absence of hyperglycemia. Alderson et al., Kidney Int. 63:2123-2133, 2003; Metz et al., J. Biol. Chem. [August 15, Epub ahead of print], 2003.
Over the years, several natural and synthetic compounds have been proposed and advanced as potential AGE/ALE inhibitors. These include aminoguanidine, pyridoxamine, OPB-9195, carnosine, metformin, as well as some angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB), derivatives of aryl (and heterocyclic) ureido, and aryl (and heterocyclic) carboxamido phenoxyisobutyric acids. Rahbar et al., Biochem. Biophys. Res. Commun. 262:651-656, 1999; Rahbar et al., Mol. Cell. Biol. Res. Commun. 3:360-366, 2000; Rahbar and Figarola, Curr. Med. Chem. (Immunol. Endocr. Metabol. Agents) 2:135-161, 2002; Rahbar and Figarola, Curr. Med. Chem. (Immunol. Endocrin. Metabol.) 2:174-186, 2002; Forbes et al., Diabetes 51:3274-3282, 2002; Metz et al., Arch. Biochem. Biophys. 419:41-49; Nangaku et al., J. Am. Soc. Nephrol. 14:1212-1222, 2003; Rahbar and Figarola, Arch. Biochem. Biophys. 419:63-79, 2003. Recently, some of these compounds were found to be effective AGE inhibitors in vivo and to prevent the development of diabetic nephropathy in a streptozotocin-induced diabetes.
Over the last decade, evidence has accumulated implicating AGEs/ALEs as major factors in the pathogenesis of diabetic nephropathy and other complications of diabetes. Administration of AGEs to non-diabetic rats leads to glomerulosclerosis and albuminuria, indicating that AGEs alone may be sufficient to cause renal injury in diabetes. Vlassara et al., Proc. Natl. Acad. Sci. USA 91:11704-11708, 1994. Diabetic animals fed with a diet low in glycoxidation products developed minimal symptoms of diabetic nephropathy compared with animals fed with diet high in glycoxidation products. Zheng et al., Diabetes Metab. Res. Rev. 18:224-237, 2002. It is widely accepted that AGEs/ALEs contribute to diabetic tissue injury by at least two major mechanisms. Browlee, Nature 414:813-820, 2001; Stith et al., Expert Opin. Invest. Drugs 11:1205-1223, 2002; Vlassara and Palace, J. Intern. Med. 251:87-101, 2002. The first is receptor-independent alterations of the extracellular matrix architecture and function of intracellular proteins by AGE/ALE formation and AGE/ALE-protein crosslinking. The other is receptor-dependent modulation of cellular functions through interaction of AGE with various cell surface receptors, especially RAGE. Wendt et al., Am. J. Pathol. 162:1123-1137, 2003; Vlassara, Diabetes Metab. Res. Rev. 17:436-443, 2001; Kislinger et al., J. Biol. Chem. 274:31740-3174, 1999.
Advanced glycation/lipoxidation endproducts (AGEs/ALEs) also have been implicated in the pathogenesis of a variety of debilitating diseases such as atherosclerosis, Alzheimer's and rheumatoid arthritis, as well as the normal aging process. The pathogenic process is accelerated when elevated concentrations of reducing sugars or lipid peroxidation products are present in the blood and in the intracellular environment such as occurs with diabetes. Both the structural and functional integrity of the affected molecules become perturbed by these modifications and can result in severe consequences in the short and long term. Because hyperlipidemia, hyperglycemia, diabetes and syndromes such as “metabolic syndrome” are common and are a common cause of morbidity and mortality, methods to counteract the symptoms and consequences of these metabolic states are needed in the art.